The objective of this proposal is to demonstrate the feasibility of using a genetically engineered monoclonal antibody (Mab) as a therapeutic for diabetic retinopathy, which is the single largest cause of new blindness in the U.S. The results of the Diabetes Control and Complications Trial have established that hyperglycemia contributes to retinopathy and that excess protein glycation (as reflected by the concentration of glycated hemoglobin) is associated with the development of retinal disease. This project derives from our extensive work delineating biologic effects of glycated albumin and the ability of A717, a Mab that site-specifically recognizes Amadori glucose adducts in glycated albumin, to neutralize these effects in vitro and in vivo. We have shown that administration of A717 to db/db mice prevents accumulation of basement membrane in the retinal capillaries. However, long-term efficacy studies, with appropriate functional and morphologic endpoints, require rat models that develop retinopathic changes. Murine antibodies will elicit a brisk anti-murine antibody response in rats, severely limiting their therapeutic usefulness. An attractive and viable strategy to perform necessary preclinical evaluation of genetically engineered A717 is to produce a totally "ratinized" version. The resulting antibody is essentially rat with the affinity and specificity of the original A717 antibody. Efficacy in rat models of retinopathy will provide the basis for using humanized A717 in preventing diabetic retinopathy. Given the magnitude of the problem and the fact that there is no treatment to prevent diabetic retinopathy, this project is eminently justified. PROPOSED COMMERCIAL APPLICATION Research will lead to the development of an immunocompatible therapeutic monoclonal antibody to demonstrate feasibility of anti-glycated albumin antibody as an improved therapy of diabetic retinopathy. Used as a novel biological response modifier, it will also aid in preventing the occurrence of diabetic retinopathy.